a). Field of the Invention
This invention relates to phenylene derivatives or salts thereof, which are useful as medicines.
b). Description of the Related Art
Leukotrienes (LT) are associated with causes for most inflammatory diseases, especially asthma, psoriasis, rheumatism and inflammatory colitis, and are considered to play an important role in inflammatory processes through cytopathy. Leukotrienes are principal mediators of allergy and inflammation, and therefore many substances which inhibit the action and/or syntheses of leukotrienes are useful for the treatment of these diseases.
Leukotrienes are arachidonate metabolites synthesized by 5-lipoxygenase (5-LO), and consist of two groups. One of the groups is LTB.sub.4 and has strong chemotaxis towards leukocytes. The other group is collectively called cysteine leukotrienes (CysLT) and includes LTC.sub.4, LTD.sub.4 and LTE.sub.4. As biologically active substances, they have been called "slow-reacting substances of anaphylaxis (SRS-A)" for many years. CysLT binds to their receptors in human tissues to exert its action. A selective LTD.sub.4 receptor inhibitor has been found to inhibit contracting actions of both LTC.sub.4 and LTD.sub.4 in human lung tissues, so that LTC.sub.4 is suggested to bind to the same site of a receptor as LTD.sub.4 (Buckner C. K. et al: Ann. NY Acad. Sci., 524, 181-6, 1988; Aharony D. et al.: New Trends in Lipid Mediators Research, Basel: Karger 67-71, 1989). LTE.sub.4 is also considered to act via the same receptor as LTD.sub.4, but is called a partially active substance for its lower potency.
On the other hand, histamine exhibits bronchial smooth muscle constricting action and capillaropenetration accelerating action as a result of its binding to the H.sub.1, receptor in cell membranes, and is an important mediator in allergic diseases. Histamine is believed to cause aggravation of asthmatic symptoms by its bronchoconstricting action and also to increase transudation of blood components into intercellular spacings due to accelerated capillaropenetration and hence to take part in the formation of edema seen in allergic rhinitis and conjunctivitis. For the treatment of these allergic diseases, antihistaminic agents are therefore used. These antihistaminic agents are however not considered to be significantly effective for severe allergic diseases such as asthma. Especially in a late asthmatic response of asthma, the symptom of airway constriction which is typical to asthma is observed due to infiltration of inflammatory cells on the bronchial mucosa, oversecretion of mucus and the like. Pharmaceuticals of a new type are therefore desired for its treatment.
Described specifically, a severe allergic disease such as asthma is considered to develop, as successive morbid conditions, an immediate asthmatic response such as bronchial constriction and edematous formation, in which a mediator such as histamine takes principal part, and a late asthmatic response such as airway constriction due to cell infiltration and mucus secretion in which a leukotriene or the like takes part.
For the prevention or curation of a variety of allergic diseases, especially asthma, a compound having antagonism against both an LTD.sub.4 receptor and a histamine H.sub.1, receptor is considered to become an effective pharmaceutical.
In addition to such marked peripheral action, leukotrienes have also been reported to have certain relevance to causes for cerebropathy such as cerebral ischemia and cerebral apoplexy (Masamune H. and Melvin L. S.: Ann. Rep. Med. Chem., 24, 71-79, 1989). It has also been reported that upon occurrence of procepharic ischemia, the concentration of LTC.sub.4 produced in neurocytes arises in the hippocampus (13.37.+-.0.24 pmol/g-tissue) and the cerebral cortex (3.29.+-.1.09 pmol/g) (Ohtsuki T. et al.: Am. J. Physiol., 37, H1249-57, 1995). Further, it has also been reported that intravenous administration of FPL55712, an LTD.sub.4 antagonist, after occurrence of ischemia significantly inhibited increase and aggravation of cortical edema (Watanabe T. et al.: J. Pharmacol. Exp. Ther., 271, 1624-29, 1994).
Accordingly, leukotriene receptor antagonistic compounds are considered to become effective pharmaceuticals for such cerebropathy.
It is however the current circumstances that no compound has been found with fully satisfactory antagonism against both an LTD.sub.4 receptor and a histamine H.sub.1, receptor. Further, all the LTD.sub.4 antagonists which have been developed so far contain at least one acidic group, so that these LTD.sub.4 antagonists are hydrophilic compounds having high polarity. They are thus unavoidably insufficient in absorption and brain penetration upon inhalative administration or oral administration. This is believed to have led to the increased doses of these pharmaceuticals and hence, to the development of side effects.